The basement membranes, which are specialized extracellular matrices overlying epithelial or endothelial cells, play an important role in organogenesis and cancer metastasis. How communication is mediated between basement membranes and cells, however, remains to be one of the most fundamental and unanswered questions in biology. Our research examines how one such basement membrane, namely the pial basement membrane, interacts with neural progenitors and early-born neurons to ensure proper brain development.

While characterizing a newly defined human brain malformation that predominantly disrupts the frontal cortex, we discovered that GPR56, a member of the adhesion G protein-coupled receptor (GPCR) family, is the disease-causing gene. We further demonstrated that (1) the ligand of GPR56 in the developing brain is collagen III; (2) collagen III is present in the meninges and the pial basement membrane; (3) GPR56 is expressed in neural progenitors and early-born neurons; (4) loss of GPR56 or its ligand collagen III results in the formation of neuronal ectopias on the brain surface that arise through penetrating the basement membrane, much like what is observed in cancer metastasis. Thus, our work revealed a novel receptor-ligand pair that regulates cerebral cortical development by mediating the communication between migrating neurons and the pial basement membrane. In the next phase of our research, we plan on further studying how GPR56 mediates the interaction between the early-born neurons and the pial basement membrane, in order to both define the boundary between the neocortex and the meninges and provide a framework for the developing cortex.

Although we have made some major strides in characterizing GPR56, there are a total of 33 members of the adhesion GPCR family, of which 2/3 are expressed in the central nervous system. Many of these GPCRs, are considered to be “orphaned” GPCRs, as their respective ligands are unknown. Our lab is also dedicated to characterizing these orphaned GPCRs that are essential to brain development.

To accomplish the research goals listed above, we use a combination of mouse genetics, cell biology, biochemistry, proteomics, imaging techniques, and ex vivo as well as in vivo electroporation.